Folate receptors (FRs) are receptors of oxidized folate. It is known that folate receptor isoforms FRα, FRβ, and FRγ are present in human cells (Non-Patent Document 1).
FRα is expressed on epithelial cell surfaces, and the expression level of FRα increases in various cancer cells. Recently, a Phase II clinical study of an anti-FRα antibody for ovarian cancer patients was conducted in the U.S. and the effects of the antibody were confirmed (Non-Patent Document 2). In addition, Patent Document 1 discloses a therapeutic composition for ovarian cancer comprising an anti-FRα antibody.
FRβ is unlikely to be expressed in tissues of healthy individuals, and it tends to be expressed on activated macrophage surfaces in rheumatoid arthritis synovium, osteoarthritis synovium, inflammatory tissue such as lung tissue afflicted with pulmonary fibrosis, and the like (Non-Patent Documents 3-5). Further, the present inventors produced an anti-human FRβ antibody and revealed that most cancer-related macrophages present in various cancer tissues are FRβ-expressing macrophages, and cases of pancreatic cancer in which there is an increase in the number of FRβ-expressing macrophages is associated with poor prognosis (Non-Patent Document 6). The present inventors further revealed that removal of FRβ macrophages in a malignant glioma implantation model with the use of an anti-FRβ antibody immunotoxin results in inhibition of the growth of malignant glioma (Non-Patent Document 7). Moreover, Patent Documents 2-4 disclose an antibody against FR-β, an FR-β antibody immunotoxin obtained by binding the antibody and a toxin, and therapeutic agents comprising the antibody and the immunotoxin.
As stated above, it has been known that cancer growth inhibitory effects can be obtained through monotherapy with an anti-FRα antibody or a substance to which an anti-FRβ antibody is bound, such as an anti-FRβ antibody immunotoxin. However, there have been no reports indicating that cancer growth inhibitory effects can be obtained through a combination therapy of an anti-FRα antibody or a substance to which the antibody is bound and an anti-FRβ antibody or a substance to which the antibody is bound. In addition, although FRα and FRβ are about 70% identical to each other at the amino acid level, there have been no reports on an antibody recognizing both FRα and FRβ.